CHAPTER 8 Central Nervous System Hypersomnias J

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CHAPTER 8 Central Nervous System Hypersomnias J. Cheung, C.M. Ruoff, E. Mignot The Stanford Center for Sleep Sciences and Medicine, Redwood City, CA, USA

OUTLINE

Classification of CNS Hypersomnia Diagnostic Procedures 149 Disorders 141 Individual Pathologies 152 Historical Perspectives Narcolepsy Type 1 152 and Pathophysiology 142 Narcolepsy Type 2 154 Idiopathic Hypersomnia 155 Clinical Features 145 Kleine-Levin Syndrome 155 Excessive Daytime Other CNS Hypersomnias 157 Sleepiness 145 Cataplexy 146 Treatment 159 Sleep Paralysis 148 Conclusions 163 Hypnagogic and Hypnopompic References 163 Hallucinations 149 Disrupted Nocturnal Sleep 149

CLASSIFICATION OF CNS HYPERSOMNIA DISORDERS

The International Classification of Sleep Disorders,1 currently in its third edition (ICSD-3), distinguishes eight subtypes of central nervous system (CNS) hypersomnia disorders (Table 8.1). The nosology of narcolepsy has also been revised, subdividing the disorder into type 1 and type 2 narcolepsy, replacing narcolepsy with and without cataplexy, respectively.

TABLE 8.1 ICSD 3 Classification of CNS Hypersomnias

Narcolepsy type 1 Narcolepsy type 2 Idiopathic hypersomnia Kleine–Levin syndrome Hypersomnia due to a medical disorder Hypersomnia due to a medication or substance Hypersomnia associated with a psychiatric disorder Insufficient sleep syndrome

This reflects a change of focus from diagnosis based on symptoms to diagnosis based on pathophysiology, in this case hypocretin (orexin) deficiency status. This change was predi- cated on the notion that almost all patients with cataplexy have hypocretin deficiency. In addition, “narcolepsy with cataplexy” is improper because some patients with hypocretin deficiency do not have cataplexy or have yet to develop cataplexy. Even though this revised classification focuses on pathophysiology, little evidence exists in distinguishing narcolepsy type 2 (Na-2) from idiopathic hypersomnia (IH).

HISTORICAL PERSPECTIVES AND PATHOPHYSIOLOGY

Among CNS hypersomnias, our understanding of the pathophysiology is mostly limited to Na-1. The first descriptions of narcolepsy with cataplexy were made by Westphal in 1877 and Gelineau in 1880.2,3 It was at this time that narcolepsy was first recognized as a unique syndrome distinct from epilepsy or other neurological disorders. In the late 1950s and early 1960s, a number of studies established the association between narcolepsy and REM sleep abnormalities.4,5 It was discovered that individuals with narcolepsy entered into REM sleep rapidly after sleep onset, in contrast with normal individuals who typically entered their first REM cycle 90 min after sleep onset. In 1973, the identification of a narcoleptic dog was first reported.6,7 This led to the breeding and studying of narcoleptic dog colonies with Labradors and Dobermans. Dement and Carskadon developed the MSLT, which continues to be the standard diagnostic test for narcolepsy.8 In 1983, Honda and coworkers identified the association of narcolepsy with the human leukocyte antigen locus (HLA-DR2) in a Japanese cohort.9 HLA genes encode for the major histocompatibility complexes found on the surface of antigen-presenting cells, immune cells that present antigens to other immune cells such as T cells. Mignot and coworkers later identified that HLA-DQB1*06:02 was a better marker than DR2 for narcolepsy across all ethnic groups, notably African Americans.10,11 In 1998, a hypothalamic specific neuropeptide called hypocretin/orexin was simultane- ously discovered by DeLecea et al. and Sakurai et al.12,13 Its exact function was unknown until 1999 when a mutation in the hypocretin (orexin) receptor 2 gene was identified by Lin, Mi- gnot and coworkers in canine narcolepsy,14 connecting hypocretin with sleep and narcolepsy. In 2000, Nishino et al. found undetectable levels of CSF hypocretin in human patients with

Historical Perspectives and Pathophysiology 143

cataplexy, indicating a lack of hypocretin rather than a receptor defect in human cases.15,16 Neuropathological work on human brain tissues followed and identified a loss of hypocret- inergic cells in the posterior hypothalamus in human Na-1 (Fig. 8.1).17,18 Although hypocretin deficiency has been identified as the cause of Na-1, the pathophysiologic mechanisms underlying sleepiness, cataplexy, and other REM-related disturbances are complicated and incompletely understood.

FIGURE 8.1 Hypocretin peptides and neurons in the lateral hypothalamus of narcoleptics versus controls. (A) Significant reduction of hypocretin mRNA expression in the lateral hypothalamus in a narcoleptic (left) versus a control brain (right). (B) Significant reduction of hypocretin-stained peptides in hypocretin cells (in the lateral hypothalamus) in a narcoleptic (left) versus a control brain (right). Narcoleptics have an 85–95% reduction in the number of hypocretin neurons. Source: (A) Kryger M et al. Atlas of Clinical Sleep Medicine, originally modified from Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med. 2000;6:991–997. (B) Modified from Thannickal TC, Moore RY, Nienjuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27(3):469–474.

144 8. Central Nervous System Hypersomnias

Hypocretin is a neuropeptide found in the posterolateral hypothalamus that regulates arousal, wakefulness, and appetite. The brain contains only 70,000 of these neurons on average, relatively few in terms of cell populations. Hypocretin is secreted as two homologous peptides, hypocretin-1 and 2, also known as orexin-A and B.12,13 Hypocretin neurons send axons to the entire cerebral cortex, including the brainstem and basal forebrain, with intense input to the tuberomammillary nucleus and the locus coeruleus.19 Hypocretin neurons are most active during wakefulness and silent during REM sleep. They also help maintain normal muscle tone by exciting monoaminergic neurons, motor neurons, and neurons in the ventrolateral periaqueductal gray matter/lateral pontine tegmentum (vlPAG/LPT). In Na-1, the loss of the hypocretin neurons together with strong, positive emotions can trigger cataplexy. One possibility may be that positive emotions activate neurons in the amygdala that subse- quently excite the sublaterodorsal tegmental nucleus (SLD) and inhibit the vlPAG/LPT. The SLD then excites neurons in the medial medulla and spinal cord that strongly hyperpolarize downstream motor neurons, resulting in cataplexy.20 The extremely high association between narcolepsy type 1 and the HLA-DQB1*06:02 geno- type, along with other recent findings, support the hypothesis of an autoimmune basis for the disease, with hypocretin cells as the logical target. As seen in many other autoimmune diseases, infections such as group A Streptococcus and influenza A have been identified as possible triggers for Na-1. Titers of the antistreptolysin antibodies, a marker for recent Streptococcus infection, have been found to be elevated in early onset narcolepsy cases.21 In addition, a sudden increase in the number of new narcolepsy cases was found in 2010, soon after the occurrence of the H1N1 pandemic. In China, there was a 3–5× increase in the number of children newly diagnosed with narcolepsy when compared to prior years.22 These cases ap- peared 4–6 months after the peak of H1N1 infections. In parallel with this, in both Finland and Sweden, a 10× increase in the cases of childhood-onset narcolepsy was reported a few months following vaccination with Pandemrix, a particular pH1N1 vaccine containing a potent adjuvant called AS03.23,24 Remarkably, in the positive cases who were HLA-typed, they were found to all test positive for the narcolepsy risk allele HLA-DQB1*06:02. Several other European studies later confirmed that this particular vaccine had similar effects. In monozygotic twins, there is a 25–32% concordance for narcolepsy, and first-degree rela- tives of patients with narcolepsy-cataplexy carry a 1% risk of developing the disorder, compared to 0.03% in the general population.25 To date, the HLA-DQB1*06:02 allele is the most specific genetic marker for Na-1 and is found in ∼98% of cases with CSF hypocretin-1 deficiency, compared to 12–38% in the general population, depending on ethnicity. In addition to HLA-DQB1*06:02, polymorphisms in the T-cell receptor (TCR) α- and β- locus, P2RY11 purinergic receptors, Cathepsin-H, and OX40L which are all involved in immune process- es, increase the susceptibility for Na-1.26–28 Altogether, it is thought that perhaps a peptide unique to hypocretin cells is mistakenly recognized by the immune system in the context of DQB1*06:02, which may lead to autoimmune destruction of hypocretin neurons. Secondary cases, however, referred by the ICSD-3 as narcolepsy due to a medical condition, may result from direct insults to the hypocretin system rather than an autoimmune mechanism. This is supported by cases of hypothalamic tumors seen in association with narcolepsy.29 In other cases, narcolepsy may be the result of complex genetic pathology, including disorders such as myotonic dystrophy, Prader–Willi syndrome, Niemann-Pick disease, and autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCADN).30

Clinical Features 145

In contrast to Na-1, the pathophysiologies of Na-2 and IH are unknown at the present time. There is little evidence for differentiating Na-2 (with normal CSF hypocretin-1) and IH at the clinical level. In patients with IH, reduced CSF histamine levels have been reported, which led to the suggestion that CSF histamine is a biomarker of hypersomnia. But in a recent study using a new, validated assay, Dauvilliers et al. did not find any differences in levels of CSF histamine comparing various hypersomnia disorders including IH and neurological controls.31 Similarly, other neurochemical studies measuring monoamine metabolites in the CSF have been inconclusive. In 2012, Rye et al. studied CSF samples of 32 hypersomnolent patients and found a gain of function in the GABA-A system in vitro.32 They also showed that this effect can be reversed in some cases by flumazenil, a GABA-A receptor antagonist, and improve symptoms of sleepiness in patients. The authors reasoned that the presence of a positive allosteric modulator of GABA-A receptors in hypersomnolent patients may be at play, although the molecular culprit has yet to be identified. A genome-wide association study of Japanese subjects with “essential hypersomnia,” equivalent to Na-2 and IH, identified risk alleles in three gene loci: NCKAP5, SPRED1, and CRAT.33 The role of these genes remains to be determined. Even though the pathophysiologic mechanism remains unknown, a number of neuroimag- ing studies have provided some interesting insights. Typically, patients with KLS have normal brain morphology on MRI and head CT.34 However, in functional imaging studies, consistent abnormalities have been reported. Studies utilizing single photon emission CT scanning during patients’ symptomatic periods have demonstrated hypoperfusion in the thalamus, hypothalamus, temporal lobes, orbitofrontal and parasagittal frontal lobes, basal ganglia and oc- cipital regions—thalamic hypoperfusion being most commonly found.35,36 When patients are asymptomatic, the thalamic hypoperfusion appears to resolve but persistent hypoperfusion in the mesial temporal lobe, frontal lobe, and basal ganglia has been found. It is conceivable that abnormalities in these brain regions correlate with the symptomatology seen in KLS. For instance, sensation of derealization and memory deficits may result from dysfunction in the temporal lobes, while behavioral symptoms of apathy, hyperphagia, and hypersexuality may result from abnormalities in the orbitofrontal and anterior parasagittal regions. Nevertheless, these correlations have not been confirmed.

CLINICAL FEATURES

Excessive Daytime Sleepiness The prevalence of excessive daytime sleepiness (EDS) in the general population ranges from 4% to 28%, depending on the definition used.37 EDS, a primary feature of all CNS hypersomnia disorders, is defined as an “inability to stay awake and alert during the major waking episode (typically daytime), resulting in periods of irrepressible need for sleep or unintended lapses into drowsiness or sleep.”1 Sleepiness typically occurs during monotonous, sedentary activity or after a heavy meal, but can also occur during regular activities such as talking and eating. Duration and frequency of sleepiness episodes can be variable in CNS hypersomnias. Although sleepiness is a core symptom of narcolepsy and IH, it can also be found in association with many other

146 8. Central Nervous System Hypersomnias conditions such as insufficient sleep, obstructive sleep apnea, and circadian rhythm disorders. It may also be a side effect of medication use, or it may be secondary to medical or neurological disorders. During episodes of sleepiness or “sleep attacks,” an individual may experience “microsleep''—a brief, unintended episode of sleep lasting only seconds—which can lead to domestic, occupational and vehicular accidents. Sleep attacks occur more often in narcolepsy than in IH. Naps are generally reported to be refreshing in patients with narcolepsy, while this is more variable in IH, explaining why scheduled naps are an effective behavioral management strategy in narcolepsy. Patients with IH may instead report prolonged episodes of unrefreshing sleep or “sleep drunkenness” and often wake up in a confused state. Severe sleepiness may also result in “automatic behaviors,” carrying out routine activities in a semiautomatic manner, lasting from a period of seconds to 30 min, for which patients are amnestic after the episode.

Cataplexy Cataplexy occurs in 65–75% of individuals with narcolepsy,38,39 although cases without cataplexy are being recognized with increasing frequency. In its typical presentation, cataplexy is defined as a sudden and transient loss of skeletal muscle tone triggered by strong emotions (Fig. 8.2). It is the core symptom of narcolepsy type 1 (Na-1, with hypocretin deficiency) and

FIGURE 8.2 A cataplectic episode in an adult demonstrating buckling of the knees and falling to the floor. Source: Courtesy of Overeem S, Mignot E, van Dijk JB, Lammers GJ. Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. J Clin Neurophysiol. 2001;18(2):78–105.

Clinical Features 147

FIGURE 8.3 Muscle groups affected in typical cataplexy. The most commonly affected muscle groups involve the legs/knees. Source: Modified from Anic-Labat S, Guilleminault C, Kraemer HC, et al. Validation of a cataplexy question- naire in 983 sleep disordered patients. Sleep. 1999;22(1):77–87. is almost always absent in narcolepsy type 2 (Na-2, without hypocretin deficiency). Cataplexy is most specifically triggered by positive emotions, such as laughter and joking, but can rarely occur in the context of anger or fright. A typical cataplexy episode lasts from a few seconds to a minute, and very rarely more than a minute. It most often results in buckling of the knees, head dropping, sagging of the jaw, slurred speech or weakness in the arms (Fig. 8.3).40 In the vast majority of attacks, cataplexy affects muscle groups bilaterally, although patients sometimes report one side of the body to be more involved than the other. Falls and injury are rare as patients typically have time to find support or to sit down while the attack is escalating. If time permits and reflexes can be assessed (which is rare because the duration is very brief), they are diminished or absent. Respiration is uncompromised, although choking may be reported if the head drops forward. Awareness is preserved throughout the episode. Recovery is complete and immediate. Partial attacks, for example, a brief grimace, slurred speech or facial drooping, can be quite subtle and only recognizable by an experienced observer. Given that patients rarely exhibit cataplexy during examination, the diagnosis is usually made by history. A good initial question may be: “Does anything unusual happen when you tell a joke, hear something funny or laugh?” It is also helpful to ask patients to describe their first and last episodes, where and in what kinds of situation it occurred, trying to evoke a real story rather than a textbook clinical description. In Na-1, cataplexy typically occurs within a year of the onset of excessive sleepiness,41 although cases where cataplexy has developed

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FIGURE 8.4 “Cataplectic facies” in a child watching a cartoon. Source: Courtesy from Serra L, Montagna P, Mignot E, Lugaresi E, Plazzi G. Cataplexy features in childhood narcolepsy. Mov Disord. 2008;23(6):858–865. more than 20 years after sleepiness have been described. Interestingly, the frequency of cataplexy often decreases with age. In children with narcolepsy, cataplexy can have a very atypical presentation when the onset of the disease is recent. The symptom may occur without any clear emotional trigger, although association with laughter and other typical emotions often develop in the following 6 months. In these cases, cataplexy often presents as facial hypotonia with droopy eyelids, mouth open- ing, and a protruded tongue, a symptom referred as “cataplectic facies” (Fig. 8.4). These patients may also experience “status cataplecticus,” a severe form of rebound cataplexy characterized by a string of cataplectic attacks lasting several hours per day, confining the patient to the bedroom. Status cataplecticus can also occur as a result of the abrupt withdrawal of an an- ticataplectic medication, typically an antidepressant. Although clear-cut cataplexy is a pathog- nomonic sign of Na-1, cataplexy or cataplexy-like episodes can occur in other disorders, such as Niemann-Pick disease type C, Prader–Willie and Norrie’s disease in children and DNA methyltransferase 1 (DNMT1) mutations in adults.30,42 It can also be seen in association with anti-Ma2 paraneoplastic syndrome, a rare limbic encephalitis associated with seminomas.43

Sleep Paralysis Sleep paralysis occur frequently in narcoleptic patients, either when falling asleep or upon awakening. Because many normal individuals also experience sleep paralysis, it is not a useful symptom diagnostically, especially if it occurs sporadically. In one study, 8% of the general population and 28% of students reported having isolated sleep paralysis.44 The occurrence of isolated sleep paralysis may be precipitated by stress, sleep deprivation, and an irregular sleep-wake schedule. It occurs when there is an incomplete, abrupt transition between wakefulness and REM sleep. When this happens, the individual finds himself paralyzed, unable to move the limbs, speak, or open the eyes, despite being awake and able to recall the event later. The experience may last for several minutes and can be very frightening. Breathing may appear more difficult than usual because intercostal muscles are paralyzed and the chest

Diagnostic Procedures 149 feels heavier. In some cases dream-like hallucinations can occur, making the experience even more terrifying. Sleep paralysis can be so distressing to some individuals that they may be- gin to fear going to sleep. After multiple episodes, however, patients generally learn that the episodes are benign, rarely lasting longer than a few minutes and always end spontaneously. Sleep paralysis is more frequently reported in narcolepsy than in IH. It is, however, more rarely reported in prepubertal children with Na-1 in comparison to later ages.

Hypnagogic and Hypnopompic Hallucinations Visual hallucinations either at sleep onset (hypnagogic) or upon awakening (hypnopompic) are another typical symptom of narcolepsy. The hallucinations are dream-like and may be unpleasant, pleasant or neutral. A repetitive theme may emerge and in these cases they can be very distressing, especially if they have a nightmarish quality. At times, these experiences can be so realistic that the patient may act upon them after awakening, believing them to be real. For example, patients with narcolepsy have been known to call the police convinced that intruders were in their home, only to find out it was just a hallucination or a dream afterward. Auditory hallucinations are also common and can range from simple sounds to an elaborate tune. These may then be difficult to distinguish from auditory hallucinations reported in schizophrenia, a possible comorbidity of narcolepsy, although in this case hallucinations are more likely part of a more complex network of delusions and the patient cannot be easily convinced these are just dreams. Hypnagogic and hypnopompic hallucinations can be thought of as dissociative states between sleep (dreaming) and wake, where the distinct boundary is unclear. Because hypnagogic hallucinations are at times difficult to differentiate from sleep onset mentation, or nightmares, they are not a very useful diagnostic sign, and they can also be found in IH.

Disrupted Nocturnal Sleep Even though daytime symptoms such as EDS and cataplexy are the most common chief complaints in narcolepsy, up to 80% of narcolepsy patients experience disruptions in nocturnal sleep.45 Therefore, clinicians should inquire about nocturnal symptoms as well as daytime symptoms. Patients often report more problems maintaining sleep than initiating sleep, with frequent nocturnal awakenings. Vivid dreaming, REM behavior disorder, and periodic limb movements may also disrupt patient’s sleep. It is a misconception that patients with narcolepsy sleep more than usual. In fact, despite having sleep attacks during the day, patients with Na-1 may even sleep less than normal individuals over the course of a 24 h day. Their major problem is staying awake for long periods of time without napping. Individuals with IH, on the contrary, typically report sleeping soundly and efficiently throughout the night.

DIAGNOSTIC PROCEDURES

When evaluating patients with EDS, the Epworth Sleepiness Scale (ESS) is one of the most widely used, validated, subjective self-administered questionnaires.8 When using this scale, patients rate their usual chances of dozing off or falling asleep in eight different daily situa- tions on a 4-point scale (0–3). The total ESS score is the sum of the eight item-scores and can range between 0 and 24, with a higher score reflecting a higher level of daytime sleepiness. It

150 8. Central Nervous System Hypersomnias provides a subjective measure of an individual’s usual level of daytime sleepiness and sleep propensity in daily life. The ESS has not been validated in children, and the Pediatric Daytime Sleepiness Scale is more appropriate for use in this population.46 In evaluating EDS, clinicians must differentiate sleepiness from fatigue and exhaustion, as patients often confuse the two. Fatigue presents as a lack of physical energy or body “tiredness.” The use of the Fatigue Se- verity Scale together with the ESS is often helpful in distinguishing EDS from fatigue.47 Several tests have been designed to objectively evaluate sleepiness. The multiple sleep latency test (MSLT) was first developed by Carskadon and Dement in 1977.48 It was designed to measure physiologic sleep tendencies in the absence of external alerting factors. The MSLT consists of a series of four to five napping tests conducted during the day and performed at 2 h intervals. To obtain a clinically valid MSLT, the test must be conducted under specific conditions.49 First, it is recommended that patients keep a regular sleep schedule, allowing for adequate sleep in the days leading up to the test. To ensure this, patients are often asked to complete a sleep diary or to wear a wrist actigraphy for 2 weeks prior to the MSLT. Sec- ond, patients are asked to withhold taking medications such as sedatives, stimulants, and those that affect the propensity to enter REM sleep, particularly tricyclic antidepressants and SSRIs/SNRIs, for 1–2 weeks prior to testing. Interrupting therapy too close to the test may also affect the results by creating rebound sleepiness or REM sleep. A drug screen should be performed on the morning of the test. Third, a polysomnography (PSG) study must be performed on the night preceding the MSLT test. The PSG serves to evaluate for alternative and coexisting causes of chronic daytime sleepiness, such as undiagnosed obstructive sleep apnea. It is also used to keep track of the patients’ total sleep time; ideally at least 360 min of sleep must be observed to exclude inadequate sleep as a confounder.50 Finally, the PSG is useful as patients with narcolepsy may have sleep onset REM periods (SOREMPs)—REM sleep which occurs within the first 15 min of sleep onset. During PSG and MSLT testing, the patient is monitored in a comfortable, soundproof, and dark bedroom. During the MSLT, patients are asked to stay awake between each nap. The initial nap opportunity begins 1.5–3 h after termination of nocturnal PSG, which ideally occurs at the patient’s usual wake up time. Prior to each nap, the patient is instructed to lie quietly and attempt to fall asleep. The MSLT records the latency for each 4–5 min nap opportunity (time between lights out and sleep onset). If no sleep is observed for 20 min, then the nap ends. If the patient falls asleep, then the nap continues for another 15 min to evaluate for the possibility of a SOREMP. At the end of the test, the mean sleep latency (MSL) is calculated for all naps. A MSL of 10–20 min is generally seen in healthy, rested subjects, while a MSL ≤ 8 min indicates sleepiness. This cut off is used for the diagnosis of both narcolepsy and IH, although ∼22% of the general population meets this criteria, and thus is not a very specific finding.51 More importantly, in narcolepsy, patients generally exhibit multiple SOREMPs during the test, with at least two instances during nocturnal sleep onset and daytime naps considered diagnostic for the condition (Fig. 8.5). Whereas a MSL ≤ 8 min is not a very specific finding, MSL≤ 8 min and the observation of ≥ 2 SOREMPs is only found in approximately 2–4% of the population. The PSG-MSLT has several limitations. While it has been validated in the context of Na-1, its use in diagnosis of Na-2 and IH have mostly been based on consensus and by extension. Clinicians should be mindful of the fact that SOREMPs are common in shift workers and can occur in other disorders that increase pressure for REM sleep, such as in insufficient sleep, untreated sleep apnea, or delayed sleep phase syndrome. It must also be performed free of

Diagnostic Procedures 151

FIGURE 8.5 MSLT and PSG result from a narcolepsy type 1 patient. (Top) A PSG performed the night prior to the MSLT with a SOREMP (REM sleep occurs in the first 15 min of sleep)—a common finding seen in patients with narcolepsy type 1. (Middle panels) Continuous two 30 s epochs from a MSLT recording of a narcoleptic patient showing an abrupt transition from wake to REM sleep. (Bottom) A summary report of a MSLT from a patient with a mean sleep latency of 0.4 min across five naps and five out of five recorded SOREMPs.

152 8. Central Nervous System Hypersomnias any neuroactive substances, which is often difficult for patients with psychiatric or pain disorders. Further, whereas a positive MSLT in the context of Na-1 is reliable, repeatability in the context of Na-2 or IH is extremely poor.52,53 Because there are no clear clinical differentiating features between IH and Na-2,54 the two disorders are likely best considered as a spectrum and they should be treated similarly. Another polysomnographic test which can be used in the evaluation of EDS is the maintenance of wakefulness test (MWT).55 As the name implies, the MWT assesses one’s ability to maintain wakefulness. It was developed based on the assumption that the volitional ability to remain awake provides important information regarding one’s ability to do so. The MWT is conducted during the day and a variety of protocols have been used. The recommended protocol consists of four 40 min trials performed at 2 h intervals, with the first trial beginning at 1.5–3 h after the patient’s usual wake up time. Patients are instructed to maintain wakefulness while sitting comfortably in bed in a dark room. In normal controls, the mean sleep latency (to the first epoch of sleep) in a MWT was found to be at 30.4 ± 11.2 min, and a MSL ≤ 8.0 min is considered abnormal.50 The MWT can be a useful tool in pharmacologic trials in evaluating response to a treatment for EDS, and in evaluating the risk of falling asleep associated with specific jobs or activities. A seldom-used test to document sleepiness is the continuous 24 or 36 h PSG. This test aims to obtain information about the frequency, timing and duration of daytime sleep episodes, as well as documenting nighttime sleep disruptions. This test is typically performed using ambulatory equipment. Although the test is excellent in distinguishing Na-1 from other pathology and gives detailed information on the nature of each patient’s hypersomnia, it is difficult to perform and thus rarely used. The long polysomnographic recording may capture an episode of cataplexy in the evaluation of a narcolepsy by showing the absence of chin and muscle twitches in the awake patient. Moreover, a 24 h PSG can also be used to help evaluate patients who are suspected to have IH or Kleine–Levin syndrome (KLS) while they are experiencing an episode of hypersomnia.

INDIVIDUAL PATHOLOGIES

Narcolepsy Type 1 Narcolepsy type 1 (Na-1) typically presents with a pentad of symptoms: EDS, cataplexy, sleep paralysis, hypnagogic and hypnopompic hallucinations, and disrupted nocturnal sleep. The diagnosis of Na-1 is most often apparent from the clinical history alone, notably the presence of cataplexy, which should be typical, for example, triggered by usual emotions (most often positive emotions such as laughter or joking). Patients with Na-1 also experience daily episodes of an irrepressible need to sleep or lapses into sleep, leading to naps, which are generally refreshing. Until recently (current update of the ICSD-3), Na-1 was known as narcolepsy with cataplexy but, because most of these cases are caused by a deficiency of hypothalamic hypocretin (orexin) signaling,26 it now represents cases with documented biological abnormality, even in the absence of cataplexy (Table 8.2). Given that CSF hypocretin-1 measurements are not systematically performed, a diagnosis of Na-1 can be made on the basis of both cataplexy and a positive MSLT test—these patients would be positive in most cases if the test was performed.15 It is only in cases without cataplexy that low CSF hypocretin-1 is mandated to diagnose Na-1.

min (typically

min

660 8 ≥ h polysomnographic monitoring

h sleep time is

c daytime lapses into sleep occurring for at least 3 months MSLT and nocturnal PSG combined MSLT 12–14 h) on 24 sleep of chronic (performed after correction deprivation), or by wrist actigraphy in association with a sleep log (averaged over at sleep) least seven days with unrestricted not better explained by another sleep disorder, or use of other medical or psychiatric disorder, or medications drugs A. Daily periods of irrepressible need to sleep or A. Daily periods of irrepressible Idiopathic hypersomnia (criteria A to F must be met) Idiopathic hypersomnia (criteria A B. Cataplexy is absent C. An MSLT shows fewer than two SOREMPS on An MSLT C. of at least one the following: D. The presence of ≤ shows a MSL 1. MSLT 24 2. Total ruled out is E. Insufficient sleep syndrome findings are The hypersomnolence and/or MSLT F. 1 b 110 pg/mL pg/mL > 110

a 1/3 of mean values obtained in normal subjects, then it should be reclassified as narcolepsy type 1. as narcolepsy < 1/3 of mean values obtained in normal subjects, then it should be reclassified

> 1/3 of mean values obtained in normal

ype 1, Type 2, and Idiopathic Hypersomnia ype 1, Type pg/mL or pg/mL or daytime lapses into sleep occurring for at least 3 months on a MSLT. A SOREMP on the preceding on the preceding SOREMP A on a MSLT. one of nocturnal polysomnogram may replace the SOREMPs on MSLT immunoreactivity is either immunoreactivity or subjects with the same standardized assay subjects with the same standardized not been measured or CSF not been measured not better explained by other causes such are sleep apnea, as insufficient sleep, obstructive of or the effect delayed sleep phase disorder, medication or substances their withdrawal

A. Daily periods of irrepressible need to sleep A. Daily periods of irrepressible Narcolepsy type 2 (criteria A to E must be met) Narcolepsy type 2 (criteria A SOREMPs of ≤ 8 min and two or more MSL A B. C. Cataplexy is absent D. Either CSF hypocretin-1 concentration has D. Either CSF hypocretin-1 by concentration measured hypocretin-1 findings E. The hypersomnolence and/or MSLT 110 etin-1 concentration, measured by etin-1 concentration, measured ICSD 3 Diagnostic Criteria for Narcolepsy T

daytime lapses into sleep occurring for at least 3 months 1. Cataplexy and a mean A onset REM periods (SOREMPs) on an MSLT. nocturnal polysomnogram on the preceding SOREMP one of the may replace 2. CSF hypocr immunoreactivity, assay in normal subjects with the same standardized If the CSF Hcrt-1 concentration is tested later and found to be either ≤ If cataplexy develops later, then it should be reclassified as narcolepsy type 1. as narcolepsy then it should be reclassified If cataplexy develops later, 1 h) unrefreshing naps are additional supportive clinical features. naps are Sleep drunkenness and/or long ( > 1 h) unrefreshing A. Daily periods of irrepressible need to sleep or A. Daily periods of irrepressible c TABLE 8.2 TABLE and B must be met) Narcolepsy type 1 (criteria A of one or both the following: B. The presence sleep sleep latency (MSL) of ≤ 8 min and two or more SOREMPs on the MSLT. or < 1/3 of mean values obtained pg/mL is either ≤ 110 a b

154 8. Central Nervous System Hypersomnias

Given that large scale CSF hypocretin-1 evaluation is not possible, only the prevalence of narcolepsy with cataplexy is known. It is estimated to occur in about 0.03% (1 in 3000) of individuals in the United States, Europe, and Korea.56 The prevalence of narcolepsy may be higher in Japan (0.16%), and lowest in Israel (0.0002%).57,58 There is a slight male predominance, and the age of onset varies from early childhood up to 50 years of age with a bimodal distribution, including a large peak between 15 and 25 years of age and a second, smaller peak between 35 and 45 years of age.59 Narcolepsy symptoms have been reported in patients as young as 2 years of age, and in one case of a hypocretin gene mutation, symptoms were identified at 6 months of age.60 It is also not uncommon to see a long gap, often more than 10 years, between the emergence of symptoms and the correct diagnosis, especially when cataplexy is initially absent. Increased awareness of narcolepsy among health-care professionals and the general public has helped to shorten that gap in recent decades. Epidemiological studies have shown that obesity is a common symptom in Na-1, and an unexplained increase in body weight is often seen at disease onset, especially when symptoms are acute.61 Increased frequency of several other sleep abnormalities has also been described in narcolepsy, including REM sleep behavior disorder (RBD), periodic limb movements of sleep, and sleep disordered breathing. In addition, there is an increased prevalence of depressive symptoms and anxiety disorders in patients with narcolepsy, with about 20% of patients experiencing panic attacks or social phobias.62 Ethnic differences in symptom manifestation are also seen. A recent article of a large cohort of subjects found that significant racial group differences exist around the age of symptom onset, including those of cataplexy, sleepiness, and hypnagogic hallucinations.63 In subjects with low CSF hypocretin-1, African Americans (28.3%) were 3.5 fold more likely to be without cataplexy when compared to Caucasians (8.1%). African Americans also appear to have a younger age of onset of sleepiness and higher subjective sleepiness scores when compared to other racial groups. These findings suggest that narcolepsy may present differently in African Americans, or alternatively there could be differences in referral patterns across ethnic groups.

Narcolepsy Type 2 Narcolepsy type 2 (Na-2) is characterized by EDS and ≥ 2 SOREMPs on the PSG-MSLT. Patients with Na-2 typically have elevated ESS scores. In a Japanese series, the mean ESS score in 62 patients with Na-2 was 14.9 ± 3.5, similar to the mean ESS (14.6 ± 3.7) of 52 patients with Na-1.64 By definition, cataplexy is absent in Na-2, although some atypical sensa- tions of weakness triggered by unusual emotions such as stress or anger may be reported. In contrast to Na-1, Na-2 is a more challenging diagnosis. This uncertainty arises from the nonspecific nature of the symptoms, the poor reliability of the MSLT, and the lack of a clear pathophysiology. Another problem is that some patients develop cataplexy many years after initial presentation. In these cases, should CSF hypocretin-1 have been measured, it would likely have been low and these patients would have been characterized as Na-1.65 For these reasons, clinicians must obtain a thorough history and evaluation in identifying alternative, confounding diagnoses such as insufficient sleep syndrome, shift work disorder, circadian phase delay, and obstructive sleep apnea. Na-2 is estimated to occur in approximately 0.03% of the population, although reliable data are lacking.39,66 In the Wisconsin Sleep Cohort, a population based sample of ∼1500 individuals, many of whom have been subjected to repeat

Individual Pathologies 155 sleep studies and MSLT testing, only three subjects were found to have consistent symptoms and repeat positive MSLTs that were not confounded by shift work or chronic sleep restric- tion, suggesting a prevalence of approximately 0.16–0.3%.67 Little is known about the natural history of Na-2. As mentioned previously, reliability of the MSLT in this population is poor when hypocretin deficiency is not present,53 therefore the disorder should not be considered a life-long condition. One study of 171 patients with Na-2 followed for several years found that of those with intermediate levels of CSF hypocretin-1 (between 110 and 200 pg/mL), 18% went on to develop cataplexy, but among those with normal hypocretin levels, cataplexy occurred in only one subject.65 This suggests that in some individuals with hypocretin deficiency the symptoms may develop gradually, further high- lighting the diagnostic challenge of Na-2.

Idiopathic Hypersomnia In the past, IH was considered to be a rather rare disorder characterized by hypersomnolence with long and unrefreshing naps, prolonged nocturnal sleep time, high sleep efficiency, absence of cataplexy, and great difficulty waking from sleep. More recently, an increasing number of subjects have been diagnosed with isolated daytime sleepiness documented by the MSLT, and a new category was created in the ICSD2: idiopathic hypersomnia (IH) without long sleep time. In the ICSD-3, IH is no longer separated between cases with and without long sleep time. Rather, the MSLT must either document a MSL of ≤ 8 min and less than 2 SOREMPs, or a long sleep time (24 h sleep time of ≥ 660 min) must be documented using a 24 h PSG or wrist actigraphy. In all cases, confounding disorders which might cause daytime sleepiness should be considered and excluded, particularly insufficient sleep syndrome. His- torically, two forms of IH were described.68 The monosymptomatic form was characterized by excessive daytime sleep of one to several hours duration, while the polysymptomatic form was characterized by excessive daytime sleep, prolonged nocturnal sleep and great difficulty upon awakening in the morning. The EDS experienced by IH patients is typically not as irresistible as in narcolepsy ( Table 8.3 for a comparison of clinical features seen in CNS hypersomnias). Disease onset commonly occurs between 10 and 30 years of age. A familial history in association with IH has been noted, although rigorous studies are still lacking. IH can be a disabling condition and is usually chronic, although spontaneous improvement in EDS may be observed in up to one quarter of patients. Patients often report having an extreme form of sleep inertia with tremendous difficulty waking, irritability, automatic behavior, and confusion commonly known as “sleep drunkenness.” The presence of sleep drunkenness has been reported in 36–52% of patients with IH.69,70 Patients often take long naps, longer than 60 min, and report waking unrefreshed. Patients with IH typically have a high sleep efficiency on PSG studies with≥ 90%. CSF hypocretin-1 levels are normal in IH patients. In the absence of systematic studies, the exact prevalence of IH remains to be determined.

Kleine–Levin Syndrome Kleine–Levin syndrome (KLS) is a recurrent hypersomnia that is characterized by recurrent (relapsing-remitting) episodes of severe hypersomnolence separated by intervening

156 8. Central Nervous System Hypersomnias hypocretin hypocretin deficiency and HLA- DQB1*06:02 heterogeneous DQB1*06:02 heterogeneous abnormalities in thalamus and hypothalamus have been found in imaging studies Pathophysiology 98% with Unknown, 40% with HLA- Unknown, likely Unknown, associated with automatic behavior and confusion periods of hypersomnia Neurocognitive changes Absent Absent Sleep drunkenness during Present efficiency compared to other hypersomnias Fragmented nocturnal sleep sleep Decreased May be common Not typical Not typical a Present in 74% Present in 57% Present in 32% Present in 50% Present Sleep hallucination a 67% 49% 24% Present in Present in Present in Present Uncommon Sleep paralysis , Idiopathic Hypersomnia and Kleine–Levin Syndrome (except in rare cases) Present Present Absent Absent Absent Cataplexy episodes) Present Present Present (recurrent Present Excessive daytime sleepiness Common Features of Narcolepsy

type 1 type 2 hypersomnia Data obtained from the Stanford Center for Narcolepsy Research database (unpublished). Research the Stanford Center for Narcolepsy Data obtained from TABLE 8.3 TABLE Narcolepsy Narcolepsy Idiopathic KLS a

Individual Pathologies 157

TABLE 8.4 Diagnostic Criteria for Kleine–Levin Syndrome (ICSD-3) Criteria A to E must be met: A. The patient experiences at least two recurrent episodes of excessive sleepiness and sleep duration, each persisting for 2 days to 5 weeks. B. Episodes recur usually more than once a year and at least once every 18 months. C. The patient has normal alertness, cognitive function, behavior, and mood between episodes. D. The patient must demonstrate at least one of the following during episodes: 1. Cognitive dysfunction 2. Altered perception 3. Eating disorder (anorexia or hyperphagia) 4. Disinhibited behavior (such as hypersexuality) E. The hypersomnolence and related symptoms are not better explained by another sleep disorder, other medical, neurologic, or psychiatric disorder (especially bipolar disorder), or use of drugs or medications. periods of normal behavior, in association with cognitive, psychiatric, and behavioral disturbances (Table 8.4). KLS is a rare disorder, with an estimated prevalence of 1 to 5 per million individuals.34 Most patients are teenagers at disease onset, although rare cases with onset as young as 4 years of age have been reported. KLS is uncommon in those older than age 35, and is 4× more likely to occur in males. The typical duration of an episode is, on average, 10 days (range from 2.5 to 80 days), with rare episodes lasting multiple weeks to months. The first episode is often triggered by an infection or associated with a fever. Further episodes recur every 1–12 months (median recurrence interval of 3 months). During symptomatic episodes, patients complain of sleepiness despite sleeping up to 16–21 h per day. Patients get up only to eat and void, and spend the majority of the day and night in bed. They remain arousable but are irritable if prevented from sleeping. When awake, patients become apathic and report impairment in communication, concentration, and memory. Partial or total amnesia episodes is generally reported following resolution of the episodes. Patients often withdraw from social interaction and display transient symptoms of depression and anxiety, and as such that they can be misdiagnosed with psychiatric conditions. This is an area of current debate and some researchers believe that psychiatric disease, especially bipolar disorder, may be more prominent in these individuals. The classic triad of hypersomnia, hyperphagia, and hypersexuality is only seen in a quarter of patients with KLS. The most specific findings are cognitive abnormalities, notably a sensation of depersonalization or derealization—an altered, dream-like state. Toward the end of an episode, patients may experience transient rebound insomnia. Once symptoms have completely resolved, patients may feel elated, and can sometimes border on hypomania. Patients are completely normal between episodes. KLS typically resolves after a median of 14 years from initial onset, and most adults are unaffected after age 35, although long term sequelae have been suggested by some studies, especially in patients who experience their first symptoms as adults.

Other CNS Hypersomnias The remaining categories of CNS hypersomnias represent a collection of conditions clinicians must consider and exclude when making a diagnosis of narcolepsy or IH. Hypersomnia

158 8. Central Nervous System Hypersomnias due to a medical disorder would be an appropriate diagnosis when patients’ symptoms are attributable to a coexisting medical or neurological disorder. For example, patients with sleep related breathing disorders may present with EDS. In this case, a diagnosis of hypersomnia due to a medical disorder should be made. Nevertheless, in some patients with OSA, residual EDS may exist despite adequate sleep and optimal treatment of their sleep apnea. It would be advisable to fully treat patients for at least 3 months, monitor the efficacy of treatment with compliance data download, and reassess at this time. In some cases, a positive airway pressure titration PSG should be performed to ensure adequate treatment. One should consider an alternative hypersomnia diagnosis only if the hypersomnolence persists after adequate treatment. Hypersomnolence has been described in association with a large number of other neurological and medical conditions, such as head trauma, stroke, brain tumors, encephalitis, myotonic dystrophy, multiple sclerosis, systemic infection, metabolic encephalopathy and neurodegenerative diseases such as Parkinson’s disease (PD) and Lewy body dementia (DLB). In the case of PD and DLB, pathology in the nigrostriatal pathway, pedunculopontine tegmental nucleus, ventrolateral tegmental area, basal forebrain, and thalamic nuclei can affect the regulation of sleep, wakefulness and circadian rhythm, resulting in a myriad of symptoms. In one study, nocturnal sleep fragmentation was found to occur about three times more frequently in patients with PD than in healthy controls (38.9% vs. 12%).71 Another study found that PD patients had significantly less total sleep time and reduced sleep efficiency as measured by PSG.72 Moreover, the CNS pathophysiology in PD may also affect the circadian system resulting in sleep-wake dysrhythmia. Sleepiness is common, and SOREMPs may be seen if an MSLT is performed. The sleep disturbance in PD has been demonstrated to correlate with disease severity.73 However, the cases of hypersomnolence and sedation that are due to the side effects of dopaminergic agents used for treatment of motor symptoms should be better classified as hypersomnia due to a medication or substance. For a more thorough review of sleep disorders associated with these conditions, the reader is directed to Chapter 5. In cases of post traumatic brain injury (TBI), symptoms of hypersomnolence are common, with one metaanalysis reporting a frequency of 30%.74 In some cases, injuries to hypothalamic hypocretin neurons, midbrain or the pons may impact wake-promoting systems. Further- more, it has been found that there is an increased prevalence of sleep disordered breathing in patients with TBI, at a frequency of 23–25%.75 The exact mechanism underlying the relation- ship between TBI and OSA remains unclear. Patients with symptoms of hypersomnia attributable to sedating medications, alcohol, or drugs of abuse should be diagnosed with hypersomnia due to a medication or substance. This diagnosis also includes symptoms associated with withdrawal from stimulant medications such as amphetamines. Common prescription medications associated with hypersomnolence include benzodiazepines, opioids, barbiturates, anticonvulsants, antipsychotics, anticholinergics, antihistamines, and hypnotics. Patients who suffer from a psychiatric disorder may also present with symptoms of hypersomnia. In this scenario, a diagnosis of hypersomnia associated with a psychiatric disorder would be appropriate. Psychiatric conditions most commonly associated with hypersomnolence include bipolar II disorder and atypical depression.76 Insufficient sleep syndrome is a behaviorally induced syndrome characterized by chronic sleep deprivation and EDS. It occurs when a person persistently fails to obtain the adequate

Treatment 159 amount of sleep required to maintain wakefulness, resulting in chronic sleep deprivation. A thorough review of the individual’s sleep pattern should demonstrate a significant disparity between the need for sleep and the amount actually acquired. In addition, there is often a lack of insight and the patient may not realize that they are not obtaining adequate sleep. Patients who may markedly restrict their sleep time during the workweek and significantly extend sleep on the weekends or during holidays may be at risk of this disorder. A therapeutic trial of sleep extension can reverse the symptoms and, therefore, should be recommended as an initial step. Finally, clinicians must be judicious in excluding the presence of insufficient sleep before considering other hypersomnia diagnoses.

TREATMENT

The combination of behavioral and pharmacologic treatments provides the best therapeutic option to control EDS in CNS hypersomnias. A key behavioral treatment is the maintenance of a regular, adequate sleep schedule. For patients with narcolepsy, institution of scheduled naps can be very effective in ameliorating EDS. This strategy is, however, less successful in patients with IH who typically experience unrefreshing naps. Educating the patient and family about the disorder helps promote treatment compliance and a supportive network. Patients may find helpful resources through organized patient advocacy support groups. Importantly, clinicians should provide counseling to hypersomnolent patients regarding the risk and avoidance of drowsy driving. A number of pharmacologic treatments are available to treat EDS, cataplexy, disrupted nocturnal sleep, and other REM-related phenomena. These medications include stimulants, antidepressants, and sodium oxybate (Table 8.5). As many of these medications have a significant side effect profile and a potential for abuse, clinicians need to be judicious in choosing a pharmacologic regimen, particularly if the etiology is unclear or multifactorial in nature like in Na-2 and IH. The nonamphetamine, wake-promoting agent modafinil is often considered a first line standard therapy for EDS in narcolepsy. It is sometimes more effective taken twice daily as compared to its advertised once daily dosing. Armodafinil is the R-enantiomer of modafinil and is twice as potent as modafinil at steady state. It is typically dosed once daily in the morning. Both modafinil and armodafinil are also Food and Drug Administration (FDA) -ap proved for the treatment of residual EDS in OSA and shift work disorders. Currently, they are not FDA approved for IH, although they are often prescribed off-label in these patients. One possible side effect of modafinil is the possibility of an allergic reaction, often manifesting as a rash. Clinicians and patients should also be aware that modafinil and armodafinil can decrease the efficacy of oral contraceptives due to their effect on the cytochrome P450 system, Alternative contraceptive methods should be proposed to patients who wish to remain on low dose hormonal therapy. Although the mode of action of modafinil is controversial, it is likely to act through inhibition of the dopamine transporter (DAT). The compound is of particular interest as its abuse potential is low. Amphetamines and amphetamine-like CNS stimulants are alternative effective pharmacologic treatments of EDS in narcolepsy, and have been in use since 1935. These include dextroamphetamine/amphetamine, methylphenidate, and methamphetamine. Amphetamines’ main mechanism of action is increased dopamine release, although weaker effects on the

160 8. Central Nervous System Hypersomnias

TABLE 8.5 pharmacologic Treatments for CNS Hypersomnias

Medication Pharmacologic properties Typical dosing regimen Side effects/remarks STIMULANTS

Modafinil Mode of action not completely Modafinil, 100–400 mg Headaches are common but clear, likely involves in the morning or as minimized by starting selective DA reuptake divided doses at lower doses and slow inhibition, and has (Armodafinil, 50–250 mg up-titration minimal addiction potential in the morning) May decrease efficacy Less effective than of hormonal oral amphetamine-based contraceptives stimulants Possible allergic effects (rash) Armodafinil is twice as potent at steady state Amphetamines Bind to dopamine and Dextroamphetamine Monitor blood pressure and norepinephrine transporter, (Dexedrine) heart rate preventing their reuptake. Dextroamphetamine/ Preference given to longer Substitute for monoamines amphetamine lasting formulations via vesicular monoamine (Adderall) Can be more effective than transporter, disrupt Methamphetamine methylphenidate in some storage and increase (Desoxyn) patients concentrations of 5–60 mg daily or as Methamphetamine has dopamine, norepinephrine, divided doses in all of higher brain penetration and serotonin (DA > NE the above and potency than >> 5-HT) amphetamine Methylphenidate Blocks monoamine uptake 10–60 mg daily or as Various formulas can have Increases release of divided doses different interindividual norepinephrine and effects dopamine Relatively low cost Short half-life Immediate release (5–10 Potential for addiction, mg) can be helpful on an especially for immediate as-needed basis release preparation Monitor blood pressure and More effective than modafinil heart rate ANTIDEPRESSANTS

Fluoxetine (SSRI) Selective serotonin reuptake 20–60 mg Long half-life, more stable inhibitor effect on cataplexy Active metabolite Useful with concomitant norfluoxetine has more anxiety disorder adrenergic effects Abrupt discontinuation of antidepressants may lead to rebound cataplexy Venlafaxine Selective serotonin- 37.5–150 mg, max 300 Gastrointestinal upset (SNRI) norepinephrine reuptake mg/day (main reason for inhibitor Once daily dose with discontinuation) Short half-life; extended extended release Potential withdrawal release formulation formulation side effects on abrupt preferred cessation Mild stimulant effect

Treatment 161

TABLE 8.5 pharmacologic Treatments for CNS Hypersomnias (cont.)

Medication Pharmacologic properties Typical dosing regimen Side effects/remarks Atomoxetine Selective norepinephrine 10–60 mg, usually Side effects include nausea, (NRI) reuptake inhibitor as divided doses, reduced appetite and Mild stimulant effect maximum 80 mg/day urinary retention Short half-life Monitor blood pressure and heart rate OTHER

Sodium oxybate Exact mechanism unknown 4.5–9 g (at a minimum Side effects include nausea, γ-hydroxybutyric acid (GHB) divided into bi-nightly weight loss, parasomnia, is the active ingredient doses) enuresis GHB is a gamma- Treats all aspects of aminobutyric acid narcolepsy, including (GABA-B) receptor agonist disrupted nocturnal sleep, EDS, cataplexy Use with caution in presence of hypoventilation or significant sleep apnea Immediate effects on disrupted nocturnal sleep Only FDA-indicated treatment for cataplexy Clarithromycin An antibiotic, likely acts Typical dose at 500 mg Side effects include as a negative allosteric taken with breakfast gastrointestinal distress, modulator of GABA-A and 500 mg taken with altered taste perception receptor lunch (start with a Cases of neurotoxicity Exact mechanism unclear 2-week trial period). including mania, Dose may be increased psychosis, and to as much as 1000 mg nonconvulsive status twice daily depending epilepticus had been on therapeutic reported response Metabolized via cytochrome P450 3A subfamily

release of norepinephrine and serotonin are also observed. Increased release occurs because amphetamine inhibits vesicular storage of monoamine, resulting in a reverse efflux of dopamine via DAT into the synaptic cleft. Other compounds such as methylphenidate increase dopamine transmission by inhibiting the reuptake of monoamines, thereby increasing the avail- ability of already released dopamine. As a class, these compounds have the greatest effects on EDS; however, they also have a high potential for abuse and tolerance. This is especially notable for short acting formulations. For these reasons, amphetamine-like stimulants should be prescribed at the minimum effective doses, and with caution in patients without a clear etiology.

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Sodium oxybate (γ-hydroxybutyrate) is now considered a standard therapy for narcolepsy. One advantage of the compound is that it treats multiple symptoms, including EDS, cataplexy, and disrupted nocturnal sleep. Sodium oxybate is a sedative anesthetic compound known to increase slow-wave sleep and, to a lesser extent, REM sleep. The mode of action of sodium oxybate in narcolepsy is unclear. Most studies suggest that its sedative-hypnotic effect is mediated through agonism at the GABA-B receptor.77 Sodium oxybate is FDA approved for the treatment of cataplexy in Na-1, as well as for the treatment of EDS in Na-1 and Na-2. It is taken twice nightly in divided dose because it has a short half-life (∼30 min). So- dium oxybate has been found to be effective in reducing cataplexy and sleep attacks, thereby improving patients’ overall daytime function.78 Interestingly, it may take weeks of treatment and dose adjustments to achieve a full therapeutic effect. Because of its potential for abuse and possible adverse effects with heavy sedation and respiratory depression, it is dispensed through a central pharmacy in the United States. Cataplexy can also be treated with antidepressants (although not FDA approved), which have REM-suppressing properties. Tricyclic antidepressants including imipramine, protrip- tyline, and clomipramine have been used since the 1970s and have established immediate effects on cataplexy. Unfortunately, these compounds also have significant anticholinergic side effects leading to dry mouth, tachycardia, sexual dysfunction, and difficulty with urination. SSRIs/SNRIs are also useful in the management of cataplexy and have fewer side effects than tricyclics. Among this class, venlafaxine, a serotonin-norepinephrine reuptake inhibitor (also a weak inhibitor of dopamine reuptake), is very effective and is therefore commonly used. The extended release formulation is preferred due to the drug’s short half-life. Atomoxetine, a specific noradrenergic reuptake inhibitor (NRI) is also used in the treatment of cataplexy and EDS, particularly in children. Although the mode of action of these medications in suppressing cataplexy is not known, it is speculated that increased noradrenergic and serotonergic signaling may lead to a suppression of REM sleep. In addition, tricyclics, SSRIs, and venlafaxine may be helpful in treating sleep paralysis, and hypnagogic and hypnopompic hallucinations. Clinicians and patients should be aware that although these compounds have immediate therapeutic effects, abrupt discontinuation of a chronic antidepressant therapy can trigger severe and dramatic rebound cataplexy. There are no currently FDA approved drugs for IH and, therefore, treatment is usually off-label and adapted from experience with narcolepsy patients. The use of stimulants such as modafinil are commonly prescribed. Antidepressant therapy may be useful if there is suggestion of associated anxiety or depression. Sodium oxybate, a compound primarily used for cataplexy, was also recently found to help some patients with IH.79 In another study, Trotti et al. showed that patients taking clarithromycin—a negative allosteric modulator of the GA- BA-A receptor—at a dose of 500 mg bid (taken in morning and lunch time) had significant improvement in subjective sleepiness.80 At the time of this writing, several other new compounds are currently undergoing clinical trials in the United States for narcolepsy and IH. Pitolisant, a histamine H3 receptor inverse agonist which activates histamine release in the brain, is in Phase III trial for treatment of EDS in Na-1 and Na-2. Another compound, JZP-110 ([R]-2-amino-3-phenylpropylcarbamate hydrochloride; formerly known as ADX-N05) a phenylalanine derivative that enhances dopaminergic and noradrenergic neurotransmission, is currently undergoing Phase III trial for treatment of EDS in narcolepsy and OSA. Flumazenil, a benzodiazepine antagonist, is being

REFERENCES 163 studied in patients with IH. BTD-001 (pentylenetetrazole), a GABA-A receptor antagonist, is undergoing Phase II trial for treatment of IH and Na-2. The results of drug trials in KLS patients have been inconsistent and disappointing. Un- less episodes are particularly severe and frequent, the best treatment is supportive, educating patients and parents about the disorder. Patients should be permitted to rest during the symptomatic periods; school, and work-related activities should be adjusted as well. The use of stimulant medications such as modafinil, methylphenidate, and amphetamines is rarely beneficial and may unmask cognitive and behavioral symptoms. Lithium has been proposed as a treatment option, especially in cases when episodes of recurrent hypersomnia are severe and frequent. However, in one metaanalysis it was found to be helpful in only 20–40% of cases.81,82 When lithium is used, serum levels should be between 0.8 and 1.2 mmol/L, and ongoing consultation with a psychiatrist is advised. The effects of other mood stabilizers, such as valproic acid or carbamazepine are less well documented. Antipsychotics such as risperidone have been used when prolonged psychotic symptoms are present.

CONCLUSIONS

CNS hypersomnias are a collection of disorders characterized by excessive sleepiness. Major advances in the past decade provided a better understanding of the pathophysiology of Na-1, likely mediated by hypocretin deficiency. Medications such as sodium oxybate can be very effective in treating patients with Na-1. On the other hand, a better understanding of the pathophysiology of Na-2, IH, and KLS is much needed. Research in these hypersomnia disorders will not only benefit patients but may also lead to a better understanding of funda- mental sleep-regulatory mechanisms.

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